Intravenous recombinant tissue plasminogen activator (IV rt-PA) is an effective therapy for acute ischemic stroke but has substantial limitations when used alone to open occluded major extracranial and intracranial arteries. The EMS and IMS I Pilot Studies (with over 120 subjects), as well clinical series from various centers, demonstrate that a combined intravenous (IV) and intra-arterial (IA) approach to recanalization, using rt-PA administered within three hours of onset, is as safe and may have improved efficacy as compared to full-dose IV rt-PA as administered during the NINDS rt-PA Stroke Trial. The Interventional Management of Stroke (IMS) III Trial is a randomized, open-label, multi-center study with a maximum of 900 subjects with acute ischemic stroke who are eligible to receive IV rt-PA within 3 hours of symptom onset and whose baseline NIH Stroke Scale score (NIHSSS) is equal to or greater than 10. The primary goal of the IMS III Trial is to determine if ischemic stroke subjects treated with rt-PA, utilizing a combined IV/IA approach to recanalization started within 3 hours of onset, are more likely to have a favorable outcome at 3 months (Rankin 0-2) as compared to subjects treated with standard IV rt-PA alone. The primary measures of safety will be mortality at 3 months and the presence of symptomatic ICH within the first 36 hours from randomization. In addition to other clinical and imaging endpoints, the economic impact of the IV/IA therapy will be evaluated. The study will use stratified randomization in which subjects with a baseline NIHSSS of 10-19 will be randomized in a 1:1 ratio and subjects with NIHSSS >20 will be randomized to a 2:1 ratio with more in the IV/IA group. A primary subgroup analysis will be conducted on the second stratum of subjects with an NIHSS > 20. The trial is open-label since blinding of the intervention is not possible but the primary 3-month and secondary endpoints will be done by an investigator blinded to treatment assignment.